Induction of adaptive immunity by flagellin does not require robust activation of innate immunity

• Type of Material: Article
• Authors: Catherine J. Sanders, Emory University; Luigi Franchi, University of Michigan; Felix Yarovinsky, University of Texas Southwestern Medical Center; Satoshi Uematsu, Osaka University; Shizuo Akira, Osaka University; Gabriel Nunez, University of Michigan; Andrew T Gewirtz, Emory University
• Language: English
• Date: 2009-02
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/eji.200838804/abstract
• Title of Journal or Parent Work: European Journal of Immunology
• ISSN: 0014-2980
• Volume: 39
• Issue: 2
• Start Page: 359
• End Page: 371
• Grant/Funding Information: This research utilized NIH Digestive Disease Research and Development Center (DDRDC) that is supported by NIH grant DK064399.; This work was supported by an NIH (DK061417) to A.T. Gewirtz.
• Keywords: adjuvant; profilin-like protein; dendritic cells; TLR11; cytokines; TLR4; Ipaf
• Research Categories: Health Sciences, Immunology; Biology, Microbiology; Health Sciences, Pathology

Abstract

The ability of Toll-like Receptor (TLR) agonists to promote adaptive immune responses is attributed to their ability to robustly activate innate immunity. However, it has been observed that, for adjuvants in actual use in research and vaccination, TLR signaling is dispensable for generating humoral immunity. Here, we examined the role of the TLR5 and MyD88 in promoting innate and humoral immunity to flagellin using a prime/boost immunization regimen. We observed that eliminating TLR5 greatly reduced flagellin-induced cytokine production, except for IL-18, and ablated DC maturation but did not significantly impact flagellin’s ability to promote humoral immunity. Elimination MyD88, which will ablate signaling through TLR and IL-1β/IL-18 generated by nod-like receptors (NLR), reduced, but did not eliminate flagellin’s promotion of humoral immunity. In contrast, loss of the innate immune receptor for profilin-like protein (PLP), TLR11, greatly reduced the ability of PLP to elicit humoral immunity. Together, these results indicate that, firstly, the degree of innate immune activation induced by TLR agonists may be in great excess of that needed to promote humoral immunity and, secondly, there is considerable redundancy in mechanisms that promote the humoral immune response upon innate immune recognition of flagellin. Thus, it should be possible to design innate immune activators that are highly effective vaccine adjuvants yet avoid the adverse events associated with systemic TLR activation.